Initial symptoms of mixed connective tissue disease are usually non-specific and include arthralgia, malaise, myalgia, and low-grade fever. Almost any organ system can be affected in MCTD.

Skin: The most common skin change is the Raynaud phenomenon, which is also the most common presenting feature of MCTD. Hand edema, acrosclerosis, calcinosis cutis, telangiectasia, erythema nodosum, hair loss, and vasculitis of digits are other manifestations. Discoid plaques and a malar rash similar to SLE can also occur. Nailfold changes are visible by capillary microscopy. Case reports describe panniculitis involving the abdomen, legs, and breasts.[14][15]

Joint: Joint involvement is usually more severe than in SLE. Arthritis with deformities similar to RA can also occur. Arthritis mutilans resembling psoriatic arthritis is rarely present.

Muscle: Inflammatory myopathy clinically and histologically similar to polymyositis often manifests as myalgia and is a common symptom of MCTD. Rarely myositis can also be the initial presentation.[16]

Lung: Pulmonary involvement occurs in almost 73% of patients, and dyspnea is the most common symptom. Patients can also be asymptomatic until fatal consequences arise.[17] Other symptoms include cough, pleuritic chest pain, wheeze, and hemoptysis. Pulmonary manifestations may include pleural effusion, pulmonary arterial hypertension, interstitial lung disease (ILD), pulmonary vasculitis, thromboembolic disease, alveolar hemorrhage, infections, and obstructive airway disease.[18]

Heart: Pericarditis is the most common variant of cardiac disease involving up to 40% of patients.[19] Pericardial effusion, mitral valve prolapse, myocarditis, accelerated atherosclerosis, and conduction abnormalities can also occur. 

Kidney: Renal involvement occurs in 15 to 25% of MCTD patients. Most patients are usually asymptomatic.[20] Membranous nephropathy is the most common finding. Nephropathy can sometimes be associated with significant morbidity, risk of hypertension, and chronic kidney disease often requiring dialysis.[21]

The central nervous system(CNS): Though the lack of CNS involvement is characteristic of MCTD, mild involvement has been described in about 25% of patients.[22] Trigeminal neuralgia is the most common CNS manifestation. Psychosis, convulsion, peripheral neuropathy, headache, nuchal rigidity, aseptic meningitis, and sensorineural hearing loss can also occur.

Gastrointestinal tract: Esophageal hypomotility, dilatation, and GERD are frequent features. Less common manifestations are pancreatitis, megacolon, duodenal bleeding, portal hypertension, and autoimmune hepatitis. Rarely patients can present with protein-losing enteropathy. They often have anasarca due to hypoproteinemia.[23]

Hematological involvement: Anemia and leukopenia are common, while there are also reports of thrombocytopenia.

Laboratory studies:

A complete blood count will demonstrate anemia and leukopenia in almost 75% of patients. Hypergammaglobulinemia is also present in 75% of patients with MCTD. Erythrocyte sedimentation rate presents as elevated in nearly all patients.[2] Immunological markers include high titer speckled pattern anti-nuclear antibody (usually greater than 1280), high titer anti-U1-RNP, and anti-U1 70kd antibody. 65% of patients with MCTD have positive rheumatoid factor[24], and 50% of patients have positive anti-CCP.[25] Muscle enzyme is above normal in most of the patients with features of myositis. Falsely positive VDRL and reduced level of complement levels are a feature in some patients. The antiphospholipid antibody is associated with pulmonary hypertension. Urinalysis can show proteinuria. Anti-double-stranded DNA, anticentromere, anti-Scl-70, and anti-PM-1 antibodies are usually absent.

Imaging studies:

Chest X-ray: Chest X-ray helps in evaluation for pulmonary infiltrates, pleural effusion, and cardiomegaly. Dilatation of the pulmonary artery can present in patients with pulmonary hypertension.

X-ray joints: X-ray of affected joints might reveal small, asymmetrical periarticular erosions. Soft tissue swelling, deformities, and destructive arthritis resembling psoriatic arthritis can present. Rarely periarticular osteopenia and aseptic necrosis may be found.

Echocardiogram: Echocardiogram shows Pericardial effusion, mitral valve prolapse, left ventricular hypertrophy, and changes secondary to pulmonary hypertension.

EKG: Abnormal EKG findings include hemiblock, bundle branch block, atrioventricular block, changes secondary to pericarditis, and pericardial effusion.

Pulmonary function testing: Reduction in diffusion capacity for carbon monoxide, forced vital capacity, forced expiratory volume, and six-minute walk tests occur in ILD.

Computed tomogram: High resolution computed tomogram is very sensitive in diagnosing ILD. Common findings include ground-glass opacities, linear opacities, subpleural micronodules, septal thickening, traction bronchiectasis usually with peripheral and lower lobe predominance. Honeycombing, airspace consolidation, emphysema, and centrilobular nodules are less common findings.[26]

Angiogram: Medium-sized arterial occlusions can occur in patients with Raynaud phenomenon.

Right heart catheterization: Definitive diagnosis of pulmonary hypertension in MCTD requires right heart catheterization demonstrating mean pulmonary arterial pressure at rest greater than 25mmHg.

No randomized controlled trials to guide the treatment of mixed connective tissue disease have yet taken place. The goal of therapy is to control symptoms and is directed by clinical manifestations and organ involvement. 

Raynaud phenomenon: Symptomatic management includes avoiding caffeine, smoking, cold temperature, and injuries. Oral calcium channel blockers (CCB), e.g., nifedipine, that decreases the peripheral resistance are an option. Intravenous prostaglandins and topical nitroglycerins have been found to be effective. Case reports exist of the Raynaud phenomenon responding to rituximab.[27]

Arthritis and arthralgia usually respond to NSAIDs and hydroxychloroquine. For refractory synovitis corticosteroids and methotrexate can be used.

Pleuritis, pericarditis, myositis, myocarditis, and aseptic meningitis usually respond to steroids. Steroid-sparing agents, e.g., methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil, are commonly used as a second-line agent. Steroid-resistant myositis may respond to intravenous immunoglobulin.

Pulmonary hypertension is usually less responsive to steroids. Patients who respond to a vasodilator challenge during right heart catheterization receive treatment with CCB. The efficacy of anticoagulation with warfarin is unknown. Prostaglandins (epoprostenol), endothelin receptor antagonists (ambrisentan), phosphodiesterase 5 inhibitors (sildenafil), immunosuppression with corticosteroids and cyclophosphamide are all therapeutic considerations.

Esophageal disorders also respond to steroids. Gastroesophageal reflux disease (GERD) treatment is with proton pump inhibitors (PPI), lifestyle and dietary modification, e.g., the elevation of the head of the bed and avoidance of dietary triggers. Prokinetics and gastric fundoplication are possible options for those who fail twice-daily PPI therapy. Esophageal motility disorder requires prokinetics. Patients with malabsorption should be on a lactose-free diet, and medium-chain triglycerides should substitute for long-chain fatty acids.

Autoimmune hemolytic anemia and thrombocytopenia receive initial treatment with steroids. Clinicians can consider rituximab in resistant cases.

Due to the presence of nonspecific symptoms and different organ involvement, MCTD mimics several other conditions, especially CTD. Few differential diagnoses are listed below.

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Polymyositis
• Dermatomyositis
• Scleroderma
• Bacterial infections
• Idiopathic pulmonary arterial hypertension
• Primary Raynaud disease

Mixed connective tissue disease, previously considered a mild and curable condition, can often be life-threatening. Almost one-third of patients with MCTD undergo complete resolution while another third can develop life-threatening complications. Prognosis depends on which organ is affected, the degree of inflammation, and the rate of progression of the disease. The mortality rate varies between 8 and -36%.[28] In a study done in the Hungarian population, the survival rate for 5 and 10 years after diagnosis was 98% and 96% respectively. Pulmonary hypertension is the most common cause of death. Interstitial lung disease, infections, cardiovascular diseases, and malignancies are other causes.[29] The presence of IgG anticardiolipin antibodies might be associated with severe disease.

Epitope spreading can occur during disease leading to change in clinical features. For example, a lower rate of skin sclerosis and a higher percentage of interstitial lung disease appeared in patients who had epitope spreading compared to those who did not, during a follow up of patients with MCTD.[30] Also, patients with MCTD can clinically progress to other CTD, e.g., SSc, RA, Sjogren syndrome, and SLE. On the other hand, patients with other CTD or undifferentiated CTD can eventually develop into MCTD. 

Life-threatening complications, e.g., thrombotic thrombocytopenic purpura, renal crisis, malignant hypertension, and respiratory failure secondary to pulmonary hypertension, can occur rarely. Cardiovascular complications include dilated cardiomyopathy, cardiac tamponade, coronary sclerosis with ischemic cardiomyopathy, and arrhythmias. Infections accelerate atherosclerosis, and malignancies can occur as side effects of immunosuppressives. Transverse myelitis is a rare central nervous system complication.[31]

Patient education about the disease course and management is vital to improve the quality of life. Active involvement of patients in the decision-making process should be encouraged. Patients with esophageal reflux and malabsorption should receive education about lifestyle and dietary modification. Encouraging an active lifestyle and exercise program can help symptom management in patients with arthritis. 

Mixed connective tissue disease resembles several other connective tissue diseases and is easy to misdiagnose. Diagnosis can be challenging to nurse practitioners and primary care physicians due to variable and mixed presentation and change in symptoms over time. Early diagnosis and targeted treatment are associated with a better outcome. It is crucial to recognize early signs and symptoms and make an early referral to a rheumatologist. Definitive diagnosis often requires close follow up and identification of the characteristic evolution of clinical, laboratory, and radiologic findings.

an interprofessional team approach is key to improve the quality of life. Pulmonologists, cardiologists, and other specialist referrals should be made based on organ involvement. Nurses and physicians should provide coordinated patient education to ensure patient understanding of signs and symptoms and when to seek medical attention. Pharmacists should help educate patients about the medications used and their potential adverse effects. Pain should be addressed not only with pharmacologic but also nonpharmacologic approaches, e.g., physical therapy, psychological, social, and emotional support.[32] An interprofessional team approach will result in the best outcomes for patients. [Level V]